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Proceedings of the National Academy of Sciences of the United States of America

Description:

PNAS is the world's most-cited multidisciplinary scientific serial.
It publishes high-impact research reports, commentaries, perspectives, reviews,
colloquium papers, and actions of the Academy. In accordance with the guiding
principles established by George Ellery Hale in 1914, PNAS publishes
brief first announcements of Academy Members' and Foreign Associates' more
important contributions to research and of work that appears to a Member to
be of particular importance.

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Abstract

Why T cells develop autoimmune reactivity to some antigens and tolerance to others is unknown. Various mechanisms can provide for T-cell tolerance. These include deletion in the thymus, exhaustive differentiation in the periphery, T-cell receptor and coreceptor downregulation, and anergy. Which mechanisms normally provide for tolerance to antigens expressed on specific tissues and why they sometimes fail is unclear. To understand this, we analyzed how a tissue-specific protein with defined timing and location of expression is recognized by T cells so as to induce tolerance or autoimmunity. We crossed mice expressing the simian virus 40 large tumor antigen on pancreatic acini beginning 4-25 days after birth with mice transgenic for a rearranged T-cell receptor that recognizes this antigen presented by the class I major histocompatibility complex molecule H-2Kk. No T-cell tolerance was found; rather, T-cell reactivity accompanied lymphocytic infiltration and pancreatic acinar destruction. This result argues that T cells may become spontaneously autoreactive to certain postnatally expressed peripheral proteins and that this reactivity may lead to autoimmune disease.